New natural inactivating mutations of the follicle-stimulating hormone receptor: Correlations between receptor function and phenotype

Premature ovarian failure occurs in almost 1% of women under age 40. Molecu lar alterations of the FSH receptor (FSHR) have recently been described. A first homozygous mutation of the FSHR was identified in Finland. More recen tly, we described two new mutations of the FSHR in woman presenting a parti al FSH-resistance syndrome (patient 1). We now report new molecular alterat ions of the FSHR in another woman (patient 2) who presented at the age of 1 9 with primary amenorrhea contrasting with normal pubertal development. She had high plasma FSH, and numerous ovarian follicles up to 3 mm in size wer e evidenced by ultrasonography. Histological and immunohistochemical examin ation of ovarian biopsies revealed the presence of a normal follicular deve lopment up to the antral stage and disruption at further stages. DNA sequencing showed two heterozygous mutations: Asp224Val in the extracel lular domain and Leu601Val in the third extracellular loop of FSHR. Cells t ransfected with expression vectors encoding the wild type or the mutated Le u601Val receptors bound hormone with similar affinity, whereas binding was barely detectable with the Asp224Val mutant. Confocal microscopy showed the latter to have an impaired targeting to the cell membrane. This was confir med by its accumulation as a mannose-rich precursor. Adenylate cyclase stim ulation by FSH of the Leu601Val mutant receptor showed a 12 +/- 3% residual activity, whereas in patient 1 a 24 +/- 4% residual activity was detected for the Arg573Cys mutant receptor. These results are in keeping with the fa ct that estradiol and inhibin B levels were higher in patient 1 and that st imulation with recombinant FSH did not increase follicular size, estradiol, or inhibin a levels in patient 2 in contrast to what was observed for pati ent 1. Thus, differences in the residual activity of mutated FSHR led to di fferences in the clinical, biological, and histological phenotypes of the p atient.